Submissions for variant NM_000122.2(ERCC3):c.325C>T (p.Arg109Ter)

gnomAD frequency: 0.00030  dbSNP: rs34295337

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255849	SCV000322491	pathogenic	not provided	2022-04-11	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies suggest a damaging effect: significantly reduced viability in mutant cells following DNA damage (Vijai 2016); This variant is associated with the following publications: (PMID: 26023681, 27153395, 29478780, 27356891, 30787465, 27655433, 29625052, 26689913, 31980526, 34308366, 34426522, 31589614, 33077847, 27004399)
Mendelics	RCV000986812	SCV001135945	pathogenic	Xeroderma pigmentosum group B	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175535	SCV001339151	likely pathogenic	Xeroderma pigmentosum	2020-03-09	criteria provided, single submitter	clinical testing	Variant summary: ERCC3 c.325C>T (p.Arg109X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00053 in 254390 control chromosomes (gnomAD and publications). The observed variant frequency is approximately 5-fold the estimated maximal expected allele frequency for a pathogenic variant in ERCC3 causing Xeroderma pigmentosum phenotype (0.00011), suggesting that the variant is benign. However, c.325C>T has been reported in the literature in compound heterozygosity with a reportedly pathogenic mutation in ERCC3 in at least one individual with another nucleotide-excision repair-related disorder, UV-Sensitivity Syndrome (UVSS; Calmels_2016). In addition, the variant has been detected in individuals with a personal or family history of breast and/or ovarian cancer (examples-Foley_2015, Maxwell_2016, Vijai_2016), including a patient who was diagnosed with both breast and skin cancers (Foley_2015). The variant has also been reported in at least one patient with colorectal cancer (AlDubayan_2018). The variant was detected in 3 affected individuals from the same family in a cohort of breast cancer patients of Ashkenazi Jewish backgrounds, and was found to be associated with an increased risk of breast cancer in a case-control study (OR=1.53) of individuals of Ashkenazi ethnicity (Vijai_2016). These data do not allow any conclusions about variant significance for Xeroderma pigmentosum, but suggest that the variant could confer susceptibility to cancer phenotypes. At least one publication reports experimental evidence evaluating an impact on protein function and reports that the variant conferred a significant reduction in cells' ability to repair DNA damage, which could be rescued by over-expression of the wild-type protein in-vitro (Vijai_2016). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV000986812	SCV001478117	pathogenic	Xeroderma pigmentosum group B	2020-12-15	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000255849	SCV001962282	likely pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	ERCC3: PVS1, PS3:Supporting
Invitae	RCV000255849	SCV002171696	pathogenic	not provided	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg109*) in the ERCC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC3 are known to be pathogenic (PMID: 16947863). This variant is present in population databases (rs34295337, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with breast cancer, skin cancer, and/or UV-sensitive syndrome (PMID: 26023681, 27004399, 27655433). ClinVar contains an entry for this variant (Variation ID: 265515). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000986812	SCV002557702	pathogenic	Xeroderma pigmentosum group B	2020-05-01	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 3 of 15). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (139 heterozygotes, 0 homozygotes). (P) 0507 - Identified variant type is not compatible with in silico predictions of pathogenicity. (N) 0702 - Comparable variants have strong previous evidence for pathogenicity (Oh, K. et al. (2006); ClinVar). (P) 0803 - Low previous evidence of pathogenicity in unrelated individuals (Calmels, N. et al. (2016); ClinVar). (P) 1001 - Strong functional evidence supporting abnormal protein function (Calmels, N. et al. (2016); Vijai, J. et al. (2016)). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) – Benign
Fulgent Genetics, Fulgent Genetics	RCV002487171	SCV002786539	likely pathogenic	Xeroderma pigmentosum group B; Trichothiodystrophy 2, photosensitive	2022-04-12	criteria provided, single submitter	clinical testing
Reproductive Health Research and Development, BGI Genomics	RCV000986812	SCV001142322	likely pathogenic	Xeroderma pigmentosum group B	2020-01-06	no assertion criteria provided	curation	NM_000122.1:c.325C>T in the ERCC3 gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is present on the biological trascript and predicted to undergo nonsense-mediated mRNA decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000255849	SCV001744195	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000255849	SCV001929949	pathogenic	not provided		no assertion criteria provided	clinical testing